The continuous intravenous infusion of phencyclidine (PCP) via an intrajugular cannula in free-roaming male Sprague Dawley rats will be used for the rapid induction of tolerance to the PCP-impaired forced motor activity. PCP (40 mg/kg/24 hours) will be infused for 3 1/2 and 7 days and performance of forced motor activity will be tested by means of an accelerating rotarod and the intravenously administered PCP test dose (2mg/kg) before and after the infusion periods. Extinction of tolerance to this effect will be followed for three weeks after the completion of the infusion. We also propose to study the contribution of pharmacokinetic mechanisms to the total tolerance developed to PCP-impaired forced motor activity by comparing the rates of disappearance of PCP from the blood, brain and peripheral tissues after the PCP test dose (2 mg/kg i.v.) in naive rats and rats infused with PCP (40 mg/kg/24 hours) or with 0.9% NaCl solution for 7 days. In addition, the in vitro hepatic PCP metabolism and the in vitro activities of microsomal aniline hydroxylase and hexobarbital oxidase will be determined in PCP-infused rats and in pair-fed, saline-infused controls. PCP concentrations in the blood, brain and peripheral tissues (liver, lung, spleen, heart, kidney, submaxillary gland, stomach, stomach contents, small intestine, mesenteric fat and neck fat) will be measured 30 min., l hr., 3,6,9,15 and 24 hours after a single intravenous bolus (2 mg/kg or l0 mg/kg) and after the chronic intravenous infusion (40 mg/kg/24 hours) for 3 1/2 and 7 days. The development of physical dependence to PCP will be assessed by the presence of withdrawal symptoms during the post-infusion period following the termination of the 8 day intravenous infusion. Since the histopatholohy of PCP in man and animals has not yet been studied, the histological examination of the bran and peripheral tissues from PCP infused and control animals will be undertaken in collaboration with Dr. S.M. Nakeeb, Director of Laboratory Animals Facilioties, SUNYAB. Finally, we propose to explore whether PCP shares certain effects on endocrine function with other abused CNS depressant drugs such as heroin, methadone and alcohol, and with neurotoxic agents that are not clear-cut CNS depressants such as tetrahydrocannabinol. Thus, we will determine the plasma testosterone concentrations by radioimmunoassay after the acute and chronic administration of PCP.